The technical challenges for a polymer-based sustained-release dosage form of peptide or other water soluble ingredients comprise initial burst release, incomplete release, delayed release in the initial or any other dosing period, and degradation of the active ingredients due to acidity or generated from the polymer degradation. To ensure that the sustained-release dosage form injectable, the drug carrying polymers are often formulated to microsphere form, tens of microns in diameter, by which the active ingredients are microencapsulated. In this case, encapsulation efficiency and size control of the microspheres become a critical for therapeutically practical dosage forms. While several peptide-loaded microsphere formulations are available on the market, the above-mentioned issues have not yet been well addressed. This situation is especially true for exenatide microsphere formulation currently sold in the market, which released exenatide for a period of a week since the third week after administration. The present invention teaches microsphere composition and its formulation method for which the problems associated with microsphere formulation, especially for peptides and exenatide will be resolved.
Microspheres are formulated with a variety of reported methods, such as the solvent evaporation, coacervation, spray drying, spray freeze-drying, ultrason-assisted atomization, and microfluidization. One of the most commonly used process involves solvent evaporation or extraction after the embryonic microspheres are formed through initial emulsification of a drug-loaded polymer solution in a continuous phase which is immiscible with the polymer solution. In case that the peptides or other ingredients are in aqueous solution form, multiplexing emulsification, an emulsion is emulsified into another continuous phase is required.
Single emulsification method is only feasible for encapsulation of lipophilic ingredients which may dissolve in an organic solvent together with the polymer which offers controlled release barrier. The co-solution is then dispersed in the aqueous phase to form embryonic microspheres, followed by organic solvent removal, through evaporation or extraction, to solidify the microspheres. In most of cases, however, biologic agents such as proteins and peptides dissolves only in water, double emulsification has to be applied. If the later continuous phase is water based, the protein or peptide solution entrapped by the organic polymer droplets may leak into the aqueous continuous phase, causing reduced encapsulation efficiency. For proteins possessing susceptible conformation, the organic/water interface may be hazardous to cause protein denaturing and aggregation.
To avoid leaking of the active ingredients into the continuous phase during the microencapsulation process, non-aqueous liquids immiscible with the polymer solution, such silicone oil, are used as the later continuous phase to emulsify the drug loaded polymer solution. Since most of proteins and peptides do not dissolve in silicone oil, encapsulation efficiency may be improved substantially. The major drawback of using silicone oil, or other non-water continuous phase is to get rid of the oily material from the microspheres surfaces. Considerable amount of organic solvents miscible with silicone oil have to be used to clean the microspheres, a highly environment unfriendly process.
Another alternative to improve encapsulation efficiency is to pre-formulate the protein or peptide ingredient to solid particles prior to microencapsulation. This microsphere forming process is called “solid-in-oil-in-water” (S/O/W) method. S/O/W method will be used in the present invention wherein the process to convert the proteins or peptides to solid form is novel.
For injection convenience, the diameter of the microspheres range between few to 200 μm, preferably within 20-100 μm in most of cases. Therefore, the primary particles of proteins or peptides to be encapsulated must be substantially smaller than the microspheres of final form. It is reasonable if the diameters of the solid protein or peptide particles is adjusted to be few microns or below.
To reduce the sizes of the primary particles, some researchers precipitated polypeptides by adding water-miscible but less polar solvents into the aqueous solution of the peptides. These water miscible solvents are, however, less volatile, and difficult to be removed by evaporation. In this case, extraction becomes more efficient for solvent removal.